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Query: UMLS:C0085110 (SCID)
 11,041 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The SCID-hu mouse implanted with human fetal tissue is a novel model for investigating human viral pathogenesis. Infection of human skin implants was used to investigate the basis for the clinical attenuation of the varicella-zoster virus (VZV) strain, V-Oka, from which the newly licensed vaccine is made. The pathogenicity of V-Oka was compared with that of its parent, P-Oka, another low-passage clinical isolate, strain Schenke (VZV-S), and VZV-Ellen, a standard laboratory strain. The role of glycoprotein C (gC) in infectivity for human skin was assessed by using gC-negative mutants of V-Oka and VZV-Ellen. Whereas all of these VZV strains replicated well in tissue culture, only low-passage clinical isolates were fully virulent in skin, as shown by infectious virus yields and analysis of implant tissues for VZV DNA and viral protein synthesis. The infectivity of V-Oka in skin was impaired compared to that of P-Oka, providing the first evidence of a virologic basis for the clinical attenuation of V-Oka. The infectivity of V-Oka was further diminished in the absence of gC expression. All strains except gC-Ellen retained some capacity to replicate in human skin, but cell-free virus was recovered only from implants infected with P-Oka or VZV-S. Although VZV is closely related to herpes simplex virus type 1 (HSV-1) genetically, experiments in the SCID-hu model revealed differences in tropism for human cells that correlated with differences in VZV and HSV-1 disease. VZV caused extensive infection of epidermal and dermal skin cells, while HSV-1 produced small, superficial lesions restricted to the epidermis. As in VZV, gC expression was a determinant for viral replication in skin. VZV infects human CD4+ and CD8+ T cells in thymus/liver implants, but HSV-1 was detected only in epithelial cells, with no evidence of lymphotropism. These SCID-hu mouse experiments show that the clinical attenuation of the varicella vaccine can be attributed to decreased replication of V-Oka in skin and that tissue culture passage alone reduces the ability of VZV to infect human skin in vivo. Furthermore, gC, which is dispensable for replication in tissue culture, plays a critical role in the virulence of the human alphaherpesviruses VZV and HSV-1 for human skin.
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PMID:Attenuation of the vaccine Oka strain of varicella-zoster virus and role of glycoprotein C in alphaherpesvirus virulence demonstrated in the SCID-hu mouse. 944 89

Macrophage (M phi) activation, as measured by cell surface expression of MHC class II, was examined during infection of immunocompetent and immunocompromised mice with murine cytomegalovirus (MCMV). Intraperitoneal infection of CB17 SCID mice with 10(6) PFU of MCMV elicited a large population of M phi which expressed low levels of MHC class II. This was surprising since infection of SCID mice with lower doses (e.g., 10(4) PFU) of MCMV elicits M phi expressing high levels of MHC class II (M. T. Heise and H. W. Virgin, J. Virol. (1995) 69, 904-909). In vivo administration of recombinant mouse IFN gamma resulted in high levels of MHC class II expression on M phi from control but not MCMV-infected SCID mice, suggesting that MCMV infection generates a state in which IFN gamma is not effective at activating M phi. The effect of MCMV infection was MHC class II specific, since MHC class I and ICAM-1 levels were increased on M phi expressing low levels of MHC class II. Interference with IFN gamma action was not due to productive or abortive infection of M phi. This suggested that MCMV infection induces a soluble factor that alters M phi responsiveness to IFN gamma. Infection of SCID mice with 10(6) PFU of MCMV induced higher levels of serum IFN alpha beta (one candidate for inhibition of IFN gamma induction of MHC class II expression) than infection with 10(4) PFU. We therefore evaluated the role of MCMV-induced IFN alpha beta on IFN gamma responses of bone marrow-derived (BMM phi) or thioglycollate-elicited M phi in vitro. Infection of normal M phi with MCMV at a low m.o.i. (0.1 to 0.2) impaired IFN gamma-mediated induction of M phi MHC class II expression, but not MHC class I expression. Inhibition of IFN gamma responses was not observed in M phi from mice with a null mutation in the IFN alpha beta receptor (IFN alpha beta R-/-). To test the in vivo relevance of virus-induced IFN alpha beta to IFN gamma-mediated responses, the kinetics of MHC class II induction during MCMV infection of IFN alpha beta R-/- mice was evaluated. MCMV-infected IFN alpha beta R-/- mice mounted an earlier M phi MHC class II response than normal mice. We conclude that MCMV infection specifically impairs IFN gamma-mediated MHC class II expression on M phi and that induction of IFN alpha beta is one mechanism by which this inhibition occurs.
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PMID:Murine cytomegalovirus infection inhibits IFN gamma-induced MHC class II expression on macrophages: the role of type I interferon. 949 8

Microsporidia (phylum Microspora) are obligate intracellular protozoan parasites that infect a wide range of vertebrate and invertebrate hosts. Over 1000 species have been classified into approximately 100 genera, and at least 13 species have been reported to infect mammals. Phylogenetically, the microsporidia are early eukaryotes because they have a true nucleus, possess prokaryote-like ribosomes, and lack mitochondria. The species that infect mammals are relatively small, measuring 2.0-7.0 microns long and 1.5-5.0 microns wide. The mature organism is the spore, which is enclosed by a chitinous coat, making it relatively resistant to the environment. Infections often occur by fecal-oral or urinary-oral transmission, although vertical transmission is quite common in the carnivores. Host cells become infected through a process of germination in which the spore propels its contents through the everting and unwinding polar filament into the host cell. The polar filament is unique to the microsporidia. With a few exceptions, microsporidiosis is typically chronic and subclinical in immunologically competent hosts. Young carnivores infected with microsporidia, however, develop severe and sometimes lethal renal disease, and immunodeficient laboratory animals (e.g. athymic and SCID mice) develop ascites and die from microsporidiosis. This review describes the morphology, life cycle, taxonomy, and host-parasite relationships of the species of microsporidia that infect mammals.
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PMID:Biology of microsporidian species infecting mammals. 955 77

Infection of the mouse cornea with herpes simplex virus (HSV) results in an immunopathologic disease of the eye termed herpetic stromal keratitis (HSK), in which the principal orchestrator is the CD4+ T cell. The mouse genotype largely determines susceptibility or resistance to HSK. BALB/c mice (H2dIgh-1a) are susceptible, while its congenic C.B-17 strain (H2dIgh-1b), which differs only in the Ig heavy chain locus, is resistant to HSK. As the magnitude and duration of viral replication as well as anti-HSV immune responses were similar in both strains, it was determined whether resistance was due to failure of CD4+ T cells to organize the immunopathologic reaction. Adoptive transfer of HSV-primed or naive CD4+ T cells from resistant C.B-17 strain into HSV-infected SCID mice resulted in HSK lesions indistinguishable from those caused by similar transfers of BALB/c CD4+ T cells. Similar results were obtained with transfers of whole T cell populations as well as with unfractionated splenocytes from the resistant mice. These results show that while intact C.B-17 mice exhibit resistance to HSK, they possess potentially pathogenic CD4+ T cells in their repertoire. The data suggest that the HSV-infected SCID mouse provides a proinflammatory microenvironment that overrides regulatory controls and/or cause activation of quiescent cells into aggressive effector T cells that orchestrate HSK.
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PMID:Immunopathology of herpetic stromal keratitis: discordance in CD4+ T cell function between euthymic host and reconstituted SCID recipients. 955 4

We examined the profile of increased intestinal muscle contractility after primary infection with Trichinella spiralis in the mouse, correlating it with parasite expulsion. We also examined the extent to which the changes in muscle contraction were T lymphocyte dependent, by infecting athymic and SCID mice. Infection was accompanied by increased tension development by intestinal muscle. Two components of this response were identified, a rapid peak increase in tension generation observed on day 6 postinfection, and a smaller but sustained increase in tension evident thereafter in euthymic BALB/c mice. The peak muscle response was significantly delayed in infected athymic and SCID mice, along with a corresponding reduction in the magnitude of the sustained component. These changes were accompanied by reduced parasite expulsion in athymic and SCID mice, compared with euthymic mice. Reconstitution of T cell function in athymic mice restored both the acute and sustained profile of muscle contraction seen in euthymic mice, and this was accompanied by faster expulsion of the worms. These results identify T cell-dependent and -independent components of the muscle response to nematode infection in the mouse and suggest that the onset of the peak contractile response, as well as the magnitude of the sustained muscle response, contributes to parasite eviction from the gut.
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PMID:T lymphocyte-dependent and -independent intestinal smooth muscle dysfunction in the T. spiralis-infected mouse. 981 46

A previous study by Kreider (Kreider et al., 1979) indicated that rabbit skin, which had been transplanted to immunodeficient nude mice, could be successfully infected with cottontail rabbit papillomavirus (CRPV). We have extended this observation in developing a rodent model for evaluation of compounds for activity against the papillomaviruses. In this model (called the SCID-Ra model), rabbit ear skin is transplanted to the dorsum of SCID mice and allowed to heal for 3 weeks. Infection with CRPV by scarification leads to the growth of warty lesions within 2 3 weeks in >95% of the animals. Topical and/or systemic therapy can be initiated at various times post infection (PI). Weekly lesion scores are recorded and compounds are evaluated for their ability to suppress wart growth when compared to untreated control mice. Ribavirin, which has had a suppressive effect both in the clinic for the treatment of respiratory papillomatosis and on the growth of warts in the rabbit back model, was evaluated and showed significant anti-proliferative activity with oral dosing. Both antiviral and antiproliferative compounds including podophyllin and 5-fluorouracil, which have been used clinically for the treatment of human papillomavirus (HPV) infections, were evaluated in this model. The anti-mitotic compound, Navelbine (vinorelbine tartrate), which is used for the treatment of non-small cell lung carcinoma was evaluated in this system and showed significant inhibition of wart growth with somewhat less topical cytotoxicity when compared to podophyllotoxin.
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PMID:Therapeutic evaluation of compounds in the SCID-RA papillomavirus model. 986 47

Infection with Chlamydia pneumoniae is a common cause of acute respiratory disease in man and is also associated with atherosclerotic cardiovascular disorder. Herein, we have compared bacterial load and immune parameters of C. pneumoniae-infected mice genomically lacking T cell coreceptors, cytokine receptors, or cytotoxic effector molecules. A protective role for CD8+ cells is shown by the enhanced severity of infection of CD8-/- or TAP-1-/-/beta2-microglobulin -/- mice. CD8+ cells hindered a parasite growth-promoting role of CD4+ T cells, as indicated by the higher sensitivity to early infection of CD8-/- than CD4-/-/CD8-/- mice, which was further confirmed in experiments in which SCID mice were reconstituted with either CD4+ or CD4+ plus CD8+ T cells. Interestingly, CD4+ T cells played a dual role, detrimental early (14 and 24 days) after infection but protective at later time points (60 days after infection). The CD8+ T cell protection was perforin independent. The early deleterious role of CD4+ in the absence of CD8+ T cells was associated with enhanced IL-4 and IL-10 mRNA levels and delayed IFN-gamma mRNA accumulation in lungs. In line with this, IFN-gammaR-/- (but not TNFRp55 -/-) mice showed dramatically increased susceptibility to C. pneumoniae, linked to reduced inducible nitric oxide synthase (iNOS) mRNA accumulation, but not to diminished levels of specific Abs. The increased susceptibility of iNOS-/- mice indicates a protective role for iNOS activity during infection with C. pneumoniae. The higher sensitivity of IFN-gammaR-/- mice to C. pneumoniae compared with that of SCID or recombination-activating gene-1-/- mice suggested a relevant protective role of IFN-gamma-dependent innate mechanisms of protection.
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PMID:Role of innate and adaptive immunity in the outcome of primary infection with Chlamydia pneumoniae, as analyzed in genetically modified mice. 1007 30

The family of the Flaviviridae contains 3 genera: (i) the hepaciviruses, to which belongs Hepatitis C virus (HCV), (ii) the flaviviruses and (iii) the pestiviruses. Over 140 million people, more than four times the number of HIV-positive individuals, are chronically infected with the HCV. Hepatitis G virus (HGV) has not yet been assigned to a genus. The impact of this recently discovered virus is yet to be established. Infections with flaviviruses such as Yellow Fever virus (YFV), Dengue Fever virus (DENV), Japanese Encephalitis virus (JEV) and Tick-borne Encephalitis virus (TBEV) are emerging world-wide. The Pestiviruses, Bovine Viral Diarrhea virus (BVDV), Classical Swine Fever virus (CSFV) and Border Disease virus (BDV) have a serious impact on life-stock. At present, only treatment with interferon, alone or combined with ribavirin, has been approved for the treatment of HCV infections. No specific antivirals are available for the treatment of infections with Hepaci-, Flavi- or Pestiviruses. Possible targets for inhibition of the replication of Flaviviridae are the binding to, and the uptake of the virus in the cell; the internal ribosomal entry site (IRES) of Hepaci- and Pestiviruses; viral proteases; the viral RNA-dependent RNA polymerase and the viral helicase. The search for specific inhibitors of HCV replication is hindered by the absence of an efficient cell culture system for propagation of this virus. In addition, small laboratory animals, including mice, are not susceptible to HCV infection. Flaviviruses may cause infection in mice, but do so mainly following direct intracerebral inoculation. We have established a small animal model for flavivirus infections in SCID mice inoculated peripherally with the murine flavivirus Modoc.
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PMID:Infections with flaviviridae. 1065 76

Bordetella bronchiseptica establishes respiratory tract infections in laboratory animals with high efficiency. Colonization persists for the life of the animal and infection is usually asymptomatic in immunocompetent hosts. We hypothesize that this reflects a balance between immunostimulatory events associated with infection and immunomodulatory events mediated by the bacteria. We have identified 15 loci that are part of a type III secretion apparatus in B. bronchiseptica and three secreted proteins. The functions of the type III secretion system were investigated by comparing the phenotypes of wild-type bacteria with two strains that are defective in type III secretion using in vivo and in vitro infection models. Type III secretion mutants were defective in long-term colonization of the trachea in immunocompetent mice. The mutants also elicited higher titres of anti-Bordetella antibodies upon infection compared with wild-type bacteria. Type III secretion mutants also showed increased lethal virulence in immunodeficient SCID-beige mice. These observations suggest that type III-secreted products of B. bronchiseptica interact with components of both innate and adaptive immune systems of the host. B. bronchiseptica induced apoptosis in macrophages in vitro and inflammatory cells in vivo and type III secretion was required for this process. Infection of an epithelial cell line with high numbers of wild type, but not type III deficient B. bronchiseptica resulted in rapid aggregation of NF-kappaB into large complexes in the cytoplasm. NF-kappaB aggregation was dependent on type III secretion and aggregated NF-kappaB did not respond to TNFalpha activation, suggesting B. bronchiseptica may modulate host immunity by inactivating NF-kappaB. Based on these in vivo and in vitro results, we hypothesize that the Bordetella type III secretion system functions to modulate host immune responses during infection.
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PMID:Modulation of host immune responses, induction of apoptosis and inhibition of NF-kappaB activation by the Bordetella type III secretion system. 1071 82

Murine gammaherpesvirus 68 (MHV68) is a gammaherpesvirus that was first isolated from murid rodents. MHV68 establishes a latent infection in the spleen and other lymphoid organs. Several gammaherpesviruses, including herpesvirus saimiri, human herpesvirus 8, and MHV68, encode proteins with extensive homology to the D-type cyclins. To study the function of the cyclin homologue, a recombinant MHV68 has been constructed that lacks the cyclin homologue and expresses beta-galactosidase as a marker (MHV68(cy-)). MHV68(cy-) grows in vitro with kinetics and to titers similar to those of the wild type. BALB/c mice infected with mixtures of equivalent amounts of the wild type and MHV68(cy-) show deficient growth of the MHV68(cy-) in an acute infection. Infection of SCID mice with virus mixtures also showed decreased MHV68(cy-) virus growth, indicating that the deficiency is not mediated by T or B cells. Although mice infected with mixtures containing 100 times as much MHV68(cy-) had greater splenic titers of the mutant virus than wild-type virus in acute infection, at 28 days postinfection splenocytes from these mice reactivated primarily wild-type virus. Quantitative PCR data indicate that equivalent genomes were present in the latent state. Reinsertion of the cyclin homologue into the cyclin-deleted virus restored the wild-type phenotype. These results indicate that the MHV68 cyclin D homologue mediates important functions in the acute infection and is required for efficient reactivation from latency.
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PMID:Murine gammaherpesvirus 68 cyclin D homologue is required for efficient reactivation from latency. 1088 40


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